Project Summary/Abstract Early trauma (ET) is a significant obstacle to alcohol recovery. Patients with alcohol use disorder (AUD) who experienced early trauma are at a higher risk of frequent and early relapse and suffer from severe clinical symptoms including emotion and stress-related difficulties. However, neural mechanisms linking alcoholism, early trauma and high relapse risk remain unclear. Two biological systems, stress-related brain circuits and the hypothalamic?pituitary?adrenal (HPA) axis system, are implicated in the pathologies of both AUD and ET. Concurrent examination of these two systems using multimodal neuroimaging techniques (e.g., simultaneous brain and stress hormone monitoring) may clarify the relationship between AUD and ET. Using this novel approach, our prior study showed that a lack of dynamic increase in the ventromedial prefrontal cortex (VmPFC) during stress was a critical predictor of ineffective coping, disrupted HPA axis response to stress, and increased alcohol consumption. Preliminary results also indicated that impaired dynamic VmPFC recovery during stress was associated with comorbid AUD/ET and early relapse. This pattern of findings leads us to hypothesize that impaired dynamic VmPFC response to stress may be a novel marker of comorbid alcoholism and early trauma, which underlies high relapse risk. Using functional magnetic resonance imaging (fMRI) combined with a prospective clinical outcome design, the proposed study aims to utilize brain-HPA axis markers of co-occurring alcoholism and early trauma and to examine whether these markers contribute to early relapse after treatment. We propose a 5-year study with four demographically-matched groups (total N=160; N=40 each; equal sex ratio); these groups will include AUD patients with and without ET and moderate drinkers with and without ET. Participants will complete an fMRI session while viewing a series of stress, alcohol, and neutral cues. After the multimodal scan, AUD patients will be engaged in eight weeks of standard, empirically-validated outpatient treatment and then prospectively followed for 90 days. To accurately capture relapse rate, we will conduct face-to-face follow-up interviews at 14, 30, and 90 days after treatment in conjunction with daily monitoring of stress and alcohol related behaviors using a smartphone app. Successful completion of the proposed aims has the potential to identify the neural mechanisms underlying comorbid alcoholism and early trauma and associated relapse risk, which may be further explored to develop new treatment targets and to improve clinical outcomes in AUD patients with early trauma.